PMID- 32655553
OWN - NLM
STAT- MEDLINE
DCOM- 20210405
LR  - 20210405
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 11
DP  - 2020
TI  - Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and 
      Exacerbates the TLR7 Agonist-Induced Lupus Mice.
PG  - 1095
LID - 10.3389/fimmu.2020.01095 [doi]
LID - 1095
AB  - Peptidylarginine deiminase 4 (PAD4), encoded by PADI4, plays critical roles in 
      the immune system; however, its contribution to the pathogenesis of lupus 
      nephritis remains controversial. The pathological roles of PAD4 were investigated 
      in lupus model mice. An imiquimod (IMQ)-induced lupus model was analyzed in 
      wild-type (WT) and Padi4-knockout (KO) mice. Proteinuria, serum anti-double 
      stranded DNA (anti-dsDNA) antibody, and renal infiltrated cells were evaluated. 
      Neutrophil migration and adhesion were assessed using adoptive transfer and 
      adhesion assay. PAD4-regulated pathways were identified by RNA-sequencing of 
      Padi4 KO neutrophils. Padi4 KO mice exhibited significant improvements in 
      proteinuria progression compared with WT mice, whereas, serum anti-dsDNA antibody 
      and immune complex deposition in the glomeruli showed no difference between both 
      mice strains. Padi4 KO mice showed decreased neutrophil infiltration in the 
      kidneys. Adoptively transferred Padi4 KO neutrophils showed decreased migration 
      to the kidneys of IMQ-treated WT mice, and adhesion to ICAM-1 was impaired in 
      Padi4 KO neutrophils. Padi4 KO neutrophils exhibited reduced upregulation of p38 
      mitogen-activated protein kinase (MAPK) pathways. Toll-like receptor 7 
      (TLR7)-primed Padi4 KO neutrophils demonstrated reduced phosphorylation of p38 
      MAPK and lower expression of JNK-associated leucine zipper protein (JLP), a p38 
      MAPK scaffold protein. Neutrophils from heterozygous Jlp KO mice showed impaired 
      adhesion to ICAM-1 and decreased migration to the kidneys of IMQ-treated WT mice. 
      These results indicated a pivotal role of PAD4-p38 MAPK pathway in renal 
      neutrophil infiltration in TLR7 agonist-induced lupus nephritis, and the 
      importance of neutrophil-mediated kidney inflammation. Inhibition of the PAD4-p38 
      MAPK pathway may help in formulating a novel therapeutic strategy against lupus 
      nephritis.
CI  - Copyright (c) 2020 Hanata, Shoda, Hatano, Nagafuchi, Komai, Okamura, Suzuki, 
      Gunarta, Yoshioka, Yamamoto and Fujio.
FAU - Hanata, Norio
AU  - Hanata N
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Shoda, Hirofumi
AU  - Shoda H
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Hatano, Hiroaki
AU  - Hatano H
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Nagafuchi, Yasuo
AU  - Nagafuchi Y
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Komai, Toshihiko
AU  - Komai T
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
FAU - Okamura, Tomohisa
AU  - Okamura T
AD  - Department of Functional Genomics and Immunological Diseases, Graduate School of 
      Medicine, The University of Tokyo, Tokyo, Japan.
FAU - Suzuki, Akari
AU  - Suzuki A
AD  - Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical 
      Sciences, Yokohama, Japan.
FAU - Gunarta, I Ketut
AU  - Gunarta IK
AD  - Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa 
      University, Kanazawa, Japan.
FAU - Yoshioka, Katsuji
AU  - Yoshioka K
AD  - Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa 
      University, Kanazawa, Japan.
FAU - Yamamoto, Kazuhiko
AU  - Yamamoto K
AD  - Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical 
      Sciences, Yokohama, Japan.
FAU - Fujio, Keishi
AU  - Fujio K
AD  - Department of Allergy and Rheumatology, Graduate School of Medicine, The 
      University of Tokyo, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200623
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Spag9 protein, mouse)
RN  - 0 (Tlr7 protein, mouse)
RN  - 0 (Toll-Like Receptor 7)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.5.3.15 (Padi4 protein, mouse)
RN  - EC 3.5.3.15 (Protein-Arginine Deiminases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Adoptive Transfer
MH  - Animals
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation
MH  - Kidney/*immunology/pathology
MH  - Lupus Nephritis/enzymology/*etiology/immunology
MH  - MAP Kinase Signaling System
MH  - Membrane Glycoproteins/*agonists
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neutrophil Infiltration/genetics/*physiology
MH  - Neutrophils/enzymology/immunology/pathology
MH  - Protein-Arginine Deiminases/deficiency/genetics/*metabolism
MH  - RNA-Seq
MH  - Toll-Like Receptor 7/*agonists
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC7324481
OTO - NOTNLM
OT  - JNK-associated leucine zipper protein
OT  - lupus nephritis
OT  - neutrophil
OT  - p38 mitogen-activated protein kinase
OT  - peptidylarginine deiminase 4
EDAT- 2020/07/14 06:00
MHDA- 2021/04/07 06:00
PMCR- 2020/01/01
CRDT- 2020/07/14 06:00
PHST- 2020/01/09 00:00 [received]
PHST- 2020/05/06 00:00 [accepted]
PHST- 2020/07/14 06:00 [entrez]
PHST- 2020/07/14 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2020.01095 [doi]
PST - epublish
SO  - Front Immunol. 2020 Jun 23;11:1095. doi: 10.3389/fimmu.2020.01095. eCollection 
      2020.